Steroid production



STEROID PRODUCTION Barney J. Magerlein, Kalamazoo, and John A. Hogg,

Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan Application December 5, 1955, Serial No. 550,818

48 Claims. (Cl. 260-2395) No Drawing.

This invention relates to a novel process for the productron of certain steroid 3-enamines and is more particularly concerned with the novel 3-amino-11-oxygenated-- 3,5,l7(20)-pregnatriene-2l-oic acid alkyl esters and with a novel method for the production and use thereof.

It is an object of the present invention to provide novel 3-amino-1 l-oxygenated-3,5, 17 (20) -pregnatriene-2loic acid alkyl esters. Another object is the provision of a process for their production. Other objects will be apparent to those skilled in the art to which this invention pertains.

According to step I of the present invention, a 3-keto- 1l-oxygenated-4,l7(20)-pregnadiene-21-oic acid ester is reacted with a secondary cyclic alkylene amine, preferably in the presence of an acid catalyst, to produce a 3-amino-1l-oxygenated-3,5,17(20)-pregnatricne 21 oic acid ester. Step II of the present invention comprises reduction of the pregnatriene-Zl-oic acid ester, with lithium aluminum hydride in an organic solvent followed by decomposition of any organo-metal complexes and excess lithium aluminum hydride present, to produce a 3-amino-11,2l dihydroxy-3,5,17(20)-pregnatriene. Step III of the present invention comprises hydrolysis of the 3-amino-ll,2ldihydroxy-3,5,17(20) pregnatriene to produce an 11,21- dihydroxy-4,17(20)-pregnadiene-3-one. While each of the steps of the process may be carried out individually, it is particularly adapted to unitary operation without isolation of intermediates, as more fully illustrated by the examples herein. These reactions, the compounds thus-produced, and a method of converting said compouds into physiologically active steroids, may be illusrtrated schematically as follows:

CH3 CH3 C O R2 0 O 0 R2 CH CH ll l Ra NE V 0: Step I R N- I II Step II LiAlH4 CH CH3 CH2 0 H (3H2 O H 23H CH ll H H O H 0 CH CH5 hydrolysis A 0: Step in R3 N IV III 3-amino-l l-oxygenated-3,5,17(20)- 2,731,343 PatentedFelo. 12, 1957 wherein R1 is an a-hydroxy group, a fi-hydroxy group, or a ketonic oxygen (=0), COOR2 is a carboxylic acid ester radical and R2 is, for example, a hydrocarbon radical, preferably containing from one to eight carbon atoms, and R3 is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, and which preferably contains less than nine carbon atoms. The ll-hydroxy group of compounds III, IV, V and VI may have either the alpha or beta configuration. Preferably the radical R2 is an alkyl radical, especially lower-alkyl.

It has been found that the process of step I of the present invention is a selective reaction. Moreover, the degree of selectivity of the reaction can be controlled. We have found that the 21-0ic acid ester function does not react to any appreciable extent with the amine reactant of the present invention until the amine has substantially completely reacted with the 3-keto function. This is surprising in view of the ease with which pyrrolidine reacts with esters to form pyrrolidyl amides. (See E. I. du Pont de Nemours and Co., New Products, Bulletin No. 28, revised May 26 1950.) Moreover, it has been found that the degree to which the starting amines undergo reaction with the 21-oic acid function can be controlled by the ratio of reactants, catalyst, reaction time, reaction temperature and choice of amine. Thus a product can be produced which has essentially no amide content or one which varies from a trace of amide to one consisting almost completely of amide, but in every case the 3-keto group is substantially completely converted to an enamine group. Examples of this controlled amide formation are given in greater detail hereinafter.

The enamine function at the 3-position of the steroid I diketo-4,17 (20)-pregnadiene-21-oic acid methyl ester,

which differs from the 3,20-ethylene glycol diketal of 11- ketoprogesterone only in the side chain, is reduced with lithium aluminum hydride under conditions identical to those used in the reduction of the diketal, about 25 percent of the lla-hydroxy isomer is obtained. Thus the A -2l-oic acid alkyl ester side chain exerts an unusual effect upon the rest of the steroid nucleus, especially on the ll-keto group. However, when the 3-ketal group of the S-ethylene glycol ketal of 3,11-diketo-4,17(20)-pregnadiene-Zl-oic acid methyl ester is replaced by a 3-pyrrolidyl group, the side chain effect is again remarkably changed. Reduction of 3-pyrrolidyl-1l-keto-3,5,17(20)- pregnatriene-Zl-oic acid methyl ester (11), for example, with lithium aluminum hydride, again under the same conditions, results in production of only a trace of 11ahydroxy isomer. Thus the combined and unpredictable effect of the presence of both the A -21-oic acid ester side chain and the 3-amino group upon the steroid compound as a Whole, is clearly manifested in an effect upon the ll-oxygen function, as evidenced by the anomalous results obtained upon reduction as described above. This unpredictable property of the compounds of the present invention, however, is an advantageous feature which is exploited in step II of the process, as the llp-hydroxy form is much more desirable for conversion to active steroid hormones in subsequent steps.

Step II of the present invention involves treatment of a 3 amino 11 oxygenated 3,5,17(20) pregnatriene- 21-oic acid ester (II) of the present invention with lithium aluminum hydride in an organic solvent, followed by hydrolysis of any excess lithium aluminum hydride and organo-rnetal complexes. In this step the 21-ester is re duced to a 21-alcohol without affecting the 3-enamine group, thus-producing a 3 amino 11,21 dihydroxy- 3,5,17(20)-pregnatriene (III). The 21-oic acid ester is reduced without afiecting the double bond conjugated to the carbonyl group and the conjugated diene system of the steroid nucleus. If the ll-oxygen function of the starting steroid is a keto group, this group is converted to an llfi-hydroxy group in the reaction, whereas if the ll-oxygen function is a hydroxy group, the hydroxy group remainsunchanged in the reaction product.

Step III of the present invention, i. e., the essentially neutral, acidic or alkaline aqueous hydrolysis of the thusproduced 3 amino 11,21 dihydroxy 3,5,17(20) pregnatriene, is productive of 11,21 dihydroxy 4, 17(20) pregnadiene-Fi-one (IV) wherein the ll-hydroxy group has the alpha or beta configuration.

Since the mixture resulting from the aqueous decomposition. of any organo-metal complexes and excess lithium aluminum hydride (step II) is alkaline, prolonged contact with the thus-produced 3 amino 11,21 dihydrew-3,5,17(20)-pregnatriene may result in the hydrolysis of the 3-amino group, thus-producing an 11,21- dihydroxy-4,17(20)-pregnadiene-3-one. In this case, step II and step III of the present invention become substantially one step since they are performed concurrently, or at least by a single continuous reaction.

These compounds (IV) or an ester thereof (V), upon treatment with osmium tetroxide form a 17,20-osmate ester which, upon treatment with an agent such as chloric acid, perchloric acid, hydrogen peroxide, pcrben zoic or peracetic acid, or the like, is converted to an 1l,17a,21- trihydroxy-4-pregnene-3,ZO-dione (VI) or an ester thereof. Thus, when the starting steroid (IV) has an 115- hydroxy group, the compound produced in this reaction is Kendalls compound F (17-hydroxycorticosterone) or an ester thereof. When the ll-hydroxy group has the alpha configuration, the compound resulting from the reactions described above can be oxidized with chromic acid, after the Zl-hydroxy group is protected by esterification, to produce an ester of cortisone. Methods are illustrated hereinafter for the conversion of the novel compounds of the present invention into cortisone or hydrocortisone.

-The starting steroids for the process of the present invention are esters of 3 keto lloc hydroxy 4,17(20)- pregnadiene 21 oic acid, of 3 keto 11/8 hydroxy- 4,1-7(20) pregnadiene 21 oic acid, and of 3,11 diketo -4,17(20) pregnadiene 21 oic acid (I). These compounds may be prepared by reacting an ll-oxygeuated 21 alkoxyoxalyl 21,21 dihaloprogesterone rep resented by the following formula:

wherein R is a-hydroxy, fl-hydroxy, or ketonic oxygen and X is chlorine or bromine, with an alkali-metal salt of an alcohol in the presence of an alcohol, e. g., sodium methoxide in methanol. These dihalo compounds are prepared by reacting lla-hydroxy, II/S-hydroxy, or 11- ketoprogesterone with an alkyl diester of oxalic acid and about one molar equivalent of an alkali-metal base, e. g., sodium methoxide, followed by the halogenation of the resulting compounds with about two molar equivalents of chlorine or bromine, all as fully illustrated in the preparations given hereinafter.

Amines which may be used in step I of the process of the present invention are pyrrolidine, piperidine, C-alkyl substituted pyrrolidines and C-alkyl substituted piperidines, e. g., 2,4-dimethylpyrrolidine, 3-propylpiperidine, Zmethylpyrrolidine, 3,4-dimethylpyrrolidine, 3-ethylpyrrolidine, 3-isopropylpyrrolidine, 3,3-dimethylpyrrolidine and other lower-alkyl C-substituted pyrrolidines and piperidines. Of these amines pyrrolidi-ne and piperidine are preferred, with pyrrolidine appearing to be the most reactive of the amines of the process of the present invention, giving consistently outstanding results, and therefore being especially preferred. The selected amine is usually used in a molar excess, calculated on the starting steroid, to achieve the optimum yield of enamine product. Although large molar equivalent excesses of an amine may be employed in the reaction, if an optimum amount of S-enarnine without a 21-amide group is the desired product, the preferred proportion of amine to starting steroid is usually from about 1.1 to about seven moles of amine per mole of steroid and especially from about 1.1 to 2.

Although the enamine formation (step I) may be conducted without a catalyst, the preferred operating conditions include the presence of a catalyst, e. g., an acid catalyst, in the reaction mixture. Catalysts which may be used include paratoluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, anhydrous hydrogen chloride, concentrated sulfuric acid, other organic and inorganic acids, and the like. Since these catalysts result in the in situ formationof a salt of the amine of the reaction, the addition of amine acid salts such as, for example, aniline sulfate, pyridine hydrochloride, pyridine para-toluenesulfonate, and the like, are also suitable catalysts. An inorganic acid salt such as, for example, sodium acid sulfate, may also be used as a catalyst. The choice of a particular catalyst does not appear to be critical since the reaction proceeds in the absence of a catalyst. However, for a substantially complete and rapid reaction, use of a catalyst, preferably a sulfonic acid, e. g., paratoluenesulfonic acid, is preferred.

Moisture in the reaction. mixture is detrimental to the procurement of high yields of product and preferred reaction conditions therefore include removal of the water formed during the enamine formation, although the reaction proceeds to a certain extent without removing the water. For optimum yields of enamine product, the water of reaction should be removed. This is conven iently accomplished by performing the reaction in a water-immiscible solvent and co-distilling the solvent and water as it is formed. Alternatively, the water may be removed by drying agents or other means and in some instances, e. g., when a small excess of amine is employed, this method is most convenient. Drying agents which may be used include calcium carbide, anhydrous calcium sulfate, and anhydrous potassium carbonate. A convenient method for the removal of the water of reaction comprises passing the refluxing solvent, either as the distilling vapor or as the condensate, or both, through a drying agent, e. g., calcium carbide, anhydrous calcium sulfate, anhydrous potassium carbonate, or the like. When about one molar equivalent of water, calculated on the starting steroid, has been removed, the reaction may be considered substantially complete. Unless an amide is the desired group at the 2l-position of the reaction product, the reaction should be interrupted at this point.

Although the reaction may sometimes be performed at room temperature or lower, it is preferably conducted above room temperature, i. e., above about 25 degrees centigrade, e. g., between about 25 and about 150 degrees centigrade, such temperature conveniently being at or about the boiling point of the reaction mixture. If the ll-oxygen function is an 11/3-hydroxy group, a reaction temperature below about 100 degrees centigrade is preferably employed since the llfi-hydroxy group may dehydrate at higher temperatures. The reaction time required for optimum yields of desired product is usually inversely related to the reaction temperature and there fore changes in reaction temperature will obviously require extended or shortened reaction times to obtain equivalent results.

Reaction times may vary between about a few minutes to several days, depending in part upon the reaction solvent, ratio of reactants, selected amine, water removal,

and the reaction product desired. When a 3-keto-11- oxygenated-4,17 (20)-pregnadiene-21-oic acid methyl ester and a large excess of pyrrolidine are reacted in refluxing benzene accompanied by removal of the water of reaction with para-toluenesulfonic acid being used as catalyst, formation of the S-enamine is substantially complete in less than one-half hour. If only one to 1.1 molar equivalents of pyrrolidine are employed, the reaction requires about 1.5 hours, under the same conditions, for completion. If an amide is the desired group at the 2l-position of the product, a large molar excess of amine and a substantially longer reaction period than required to form the 3-enarnine should be used.

Reaction solvents which may be employed are prefer ably the water-immiscible aromatic hydrocarbons and halogenated hydrocarbons, e, g., benzene, toluene, Xylene, chlorobenzene, and the like, although other solvents such as, for example, pentane, hexane, chloroform, methylene chloride, carbon tetrachloride, and the water-miscible solvents, e. g., methanol, ethanol, tertiary butyl alcohol, tetrahydrofuran, dioxane, and other solvents may be used. If a water-miscible solvent is employed, the removal of the water of reaction is conveniently achieved by the use of a drying agent.

Compounds produced by the process of step I of the invention may be represented by Formula 11. Preferred compounds are the methyl and ethyl esters of 3-amino-1 1- oxygenated-3,5,l7(20)-pregnatriene-2l-oic acids wherein the amino group is pyrrolidyl or piperidyl, since these are most readily prepared and most readily converted to cortisone or hydrocortisone as illustrated hereinafter. The especially preferred compounds of the present invention are the methyl and ethyl esters of 3-pyrrolidyl- 11-keto-3,5,l7(20)-pregnatriene-21-oic acid and of 3-pyrrolidyl-l 1-hydroxy-3,5, 17 (2O) -pregnatriene-21-oic acid wherein the ll-hydroxy group has the alpha or beta stereoconfiguration. These compounds are readily produced in substantially quantitative yield when following the preferred procedure given above.

Step II of the process of the present invention, i. e., reduction of the thus-produced 3-amino-ll-oxygenated- 3,5,17(20)-pregnatriene 2l-oic acid ester with lithium 6 aluminum hydride or equivalent reducing agent in ad organic solvent, e. g., ether, dioxane, tetrahydrofuran, benzene, hexane, mixtures of these and others, followed by hydrolysis of any excess lithium aluminum hydride or organo-metal complexes, converts the 21-oic acid ester group to a 21-hydroxy group without affecting the 3-amino group. The reaction theoretically requires three moles of lithium aluminum hydride for every four moles of steroid, but the lithium aluminum hydride is usually employed in substantial excess of this theoretical amount to ensure optimum yields of desired product. When the steroid and lithium aluminum hydride have been thoroughly mixed, preferably with cooling, the reaction is essentially complete. Continued stirring or heating or both are sometimes employed, however, to ensure completeness of reaction, although heating is usually not necessary and sometimes detrimental. The excess lithium aluminum hydride and any steroid-metal complex is decomposed by the careful addition of water to the reaction mixture. If a water-immiscible solvent is employed, the resulting steroid product may be isolated by separating the organic phase from the aqueous phase and then distilling the solvent from the separated layer, or if a water-miscible solvent is employed, by adding sufiicient water to precipitate the steroid from the mixture and thereafter separating the steroid therefrom in a conventional manner. In either case the steroid product may be recovered by distilling the organic solvent from the reaction mixture.

A preferred procedure comprises reacting the starting 3- amino-11-oxygenated-3,5,l7(20)-pregnatriene-21-oic acid ester (II) with lithium aluminum hydride in a watermiscible, non-reactive solvent, e. g., tetrahydrofuran or dioxane, at a temperature substantially below room temperature, i. e., below twenty degrees centigrade, and then decomposing any excess lithium aluminum hydride and organo-metal complexes thus-formed with water or organic carbonyl compound. A low reaction temperature ensures a minimum of side reactions and the use of a water-miscible solvent avoids a two phase solvent system. Water rather than acid is preferred for decomposition of the reaction complex since the 3-amino-ll,21-dihydroxy-3,5,l7(20)-pregnatrienes are stable under the ensuing conditions when water is used, and the decomposition, using water, is not accompanied by as great a heat of reaction as it is when acid is used for decomposition of the organo-metal complexes and any excess lithium aluminum hydride. The use of water and low decomposition temperatures is important if optimum yields of product having the 3-amino group, as is present in compound III, are to be obtained, since this group is sensitive to heat and acid in aqueous solution. Frequently, the reaction product is somewhat decomposed into noncrystalline non-identifiable products when exposed to acid and heat and the reaction is therefore preferably conducted in the absence of acid.

tep III of the process of the present invention involves reaction of the thus-produced 3-amino-l1,2l-dihydroxy-3,5,17(20)-pregnatriene with water or aqueous acid or base. This treatment removes the S-amino group and results in regeneration of the A -3-keto group in the steroid nucleus, with production of 11,2l-dihydroxy-4, 17(20)-pregnadiene-3-one. While either organic or mineral acids may be used, mineral acids do not appear to give as clear cut a reaction as organic acids, for example,

bufiered acetic acid. Bases are preferred over acids for een hours in refluxing percent methanol. If a small I amount of base is added, e. g., sodium hydroxide, potassiumcarbonate, sodium bicarbonate, or the like, thereactionis usually complete in less than an hour at about thirty. degrees centigrade. Acidification of the resulting mixture and separation of the organic layer, if waterimmiscible, or extraction of the resulting solution with methylene chloride, benzene or the like, if water-miscible, and then distilling the solvent therefrom, separates the thus-produced 11,21 dihydroxy-4,l7(20)-pregnadiene-3- one.

Reacting the thus-produced 11,2l-dihydroxy-4,17(20)- pregnadiene-3-one, or an ester thereof, with osmium tetroxide followed by chloric acid, perchloric acid, perbenzoic acid, peracetic acid, hydrogen peroxide, or the like, is productive of Kendalls compound E if the starting hydroxy steroid contains the 11p-hydroxy group, or ll-epi F if the starting steroid contains the lloz-hydroxy group, said latter compound being readily convertible to Kendalls compound E by 2l-acetylation followed by 11- oxidation as disclosed in U. S. Patent No. 2,602,769, issued July 8, 1952, to Murray and Peterson.

The following preparations and examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1.3,1 1-DIKETo-4,17 (20)-PREGNA- DIENE-Zl-OIC ACID METHYL ESTER SODIUM ENOLATE OF ll-KETO-Zl-ETHOXYOXALYL- PROGESTERONE To a mixture of 3.4 milliliters of a 3.4 normal methanolic sodium methoxide solution (0.0116 mole), 0.45 milliliter of absolute ethanol, and twenty milliliters of dry benzene, said mixture previously having been distilled until eight milliliters of distillate had been collected and then cooled, was added 2.3 miililitcrs (0.0151 mole) of ethyl oxalate and a solution of 3.28 grams (0.01 mole) of ll-ketoprogesterone in 38 milliliters of dry benzene. The solution became turbid and a yellow precipitate formed. The reaction mixture was stirred for ninety minutes, 55 milliliters of ether was then added thereto, and stirring was continued for sixty minutes, whereafter a l30-milliliter portion of ether was added thereto. The thus-formed yellow precipitate of the sodium enolate of l1-keto-2l-ethoxy-oxalylprogesterone was filtered, washed with several fifty-milliliter portions of ether, and after drying found to weigh 3.65 grams. The ether wash contained 0.54 grain of unreacted ll-ketoprogesteronc. The yield of the sodium enolate of 1l-keto-2l-ethoxyoxalylprogesterone was 81 percent of the theoretical or practically quantitative calculated on the reacted ll-kctoprogesterone. The presence of a sodium enolate was verified by the extreme solubility of the product in water and by a positive ferric chloride test for enols as exhibited by the formation of a bright red color when the product wasdissolvcd in alcoholic and aqueous ferric chloride solutions.

11-KETO-2l,'2l-DIBROMO-21-ETHOXYOXXLYL PROGESTERONE To a stirred solution of 4.50 grams (0.0l mole) of the sodium enolate of 1l-keto-Zl-cthoxyoxalylprogesterone and two grams of potassium acetate in seventy milliliters of glacial acetic acid was added 3.09 grams (1.00 milliliter; 09193 mole) or" bromine dropwise at room temperature. When the addition was compicte, the reaction mixture was mixed with a large volume of water. The aqueous layer was then decanted from the precipitated viscous yellow product which was thereafter dissolved in alcohol and reprecipituted as a white solid by the dropwise addition of water. The yield or" thusproduced 11 keto-21,2l-dibromo-2l-ethoxyoxalylprogesterone, after filtering and drying, was 4.0 grams, a yield of seventy percent of the theoretical.

8 3,11-DIKETO4,17 (20 -PREGNADIENE-21-OIC ACID METHYL ESTER To a solution of 5.90 grams (0.01 mole) of ll-keto 21,2l-dibromo-Zl-ethoxyoxalylprogesterone in milliliters of'methanol was added 3.24 grams (0.06 mole) of commercial grade sodium methoxide. The resulting admixture was maintained for three hours at about 25 degrees centigrade, whereafter the whole was diluted with water and then extracted with two portions of methylene chloride. The methylene chloride extracts were dried with anhydrous sodium sulfate and the solvent was thereafter distilled at atmospheric pressure, leaving a quantitative yield of 3.60 grams of 3,1l-diketo-4,17(20)-pregnadiene-Zl-oic acid methyl ester as an oil. This oil was dissolved in fifty milliliters of benzene and chromatogra hed over a column of grams of Florisil synthetic magnesium silicate. The column was developed with 400-milliliter portions of solvent of the following composition and order: three portions of methylene chloride, five portions of methylene chloride plus five percent acetone, and one portionof acetone. The methylene chloride plus five percent acetone eluates were combined and the solvent was removed therefrom leaving 1.5 grams of crystalline 3,11-diketo-4,17(20)-pregnadiene-2l-oic acid methyl ester which, after crystallization from acetone and Skellysolve B hexane hydrocarbons, melted at 213 to 214 degrees centigrade.

Analysis.-..Calculated for C22H2s042 C, 74.17; H, 7.92. Found: C, 74.37; H, 8.21.

Similarly, other esters of 3,11-diketo-4,l7(20)-pregnadiene21-oic acid are prepared by substituting the selected alkanol and alkali-metal salt of an alcohol for the sodium methoxide in methanol used therein, e. g., sodium ethoxide in ethanol, sodium isopropoxide in isopropanol, sodium phenoxide in tertiary butyl alcohol, potassium tertiary butoxide in tertiary butyl alcohol, lithium methoxide in methanol, sodium octanoate in tertiary butyl alcohol, andv the like, producing esters of the above-named steroid acid which are preferably alkyl and especially lower-alkyl, e. g., methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, amyl, hexyl, heptyl, octyl, and the like.

PREPARATION 2.3 -KETo-1 1tx-HYDROXY-4, 17 (20)PREGNA- DreNE-21-0rc ACID METHYL ESTER PREPARATION 3 .3 KETO1 l-fi-HYDROXY-4, 1 7(20)-PREGNA DIENE-Zl-OIC Acm METHYL ESTER In exactly the same manner as described in Preparation 1, 3-keto-1lB-hydroxy-4,17(20)-pregnadiene-21-oic acid methyl ester is prepared by substituting llfi-hydroxyprogesterone for the ll-ketoprogesterone used in the therein-described reaction as the starting steroid.

As stated before with regard to the ll-keto or 11shydroxy compounds, other esters of 3-keto-l1fi-hydroxy- 4,17(20)-pregnadiene-2l-oic acid are prepared by substituting other alkali-metal salts of other alcohols and substitutingother alcohols for the sodium methoxide and methanol used therein.

Example 1.3 -pyrr0lidyl -11 -keto -3,5,17(20) -pregnatriene-ZI-oic acid methyl ester A. A solution of one gram of 3,1 l-diketo-4,17(20)- these crystals from ethyl acetate gave crystals of 3 pyrrolidyl 11 keto-3,5,17(20)-pregnatriene-2l-oic acid methyl ester melting at 176 to 179 degrees centigrade and having the analysis given below.

Analysis-Calculated for CaeHssNOs: C, 76.24; H, 8.61; N, 3.42. Found: C, 76.34; H, 8.31; N, 3.64.

B. A solution of three grams of 3,1l-diketo-4,17(20)- pregna'diene-Zl-oic acid methyl ester, ninety milligrams of paratoluenesulfonic acid, and three milliliters of pyrrolidine in sixty milliliters of benzene was heated at its reflux temperature for one hour during which time the water formed in the reaction was removed azeotropically from the reaction mixture by the refluxing benzene. Removal of the benzene and pyrrolidine by distillation at reduced pressure, dissolving the residue in 500 milliliters of methylene chloride, and then washing the resulting solution with ice-cold base, water, and ice-cold dilute acid, and finally water, produces a solution containing a substantially quantitative yield of 3 pyrrolidyl 11 keto 3,5,17(20)-pregnatriene-2l-oic acid methyl ester which may be isolated by distillation of the solvent from the. solution.

C. The following experiments illustrate the rates at which the 3-pyrrolidyl enamine group and the 21-pyr-.

[1.1 molar equivalents of pyrrolidine, water removed by water-trap system] Percent Ennmme Reaction Time (Minutes) Formed No significant amounts of amide formed.

[1.1 molar equivalents of pyrrolidino, water removed by passing the refluxing benzene through calcium carbide] Percent Enamine Form ed Reaction Time (Minutes) Percent Amide Formed Percent Amide Formed No significant amounts of amide formed.

[2.0 molar equivalents of pyrrolidine, water removed by water-trap system] Percent Amide Formed Percent Enamine Example 2.3- piperidyl- 11- keto- 3,5,17(20)- pregnatriene-ZI -0z'c acid methyl ester In the same manner as described in Example 1, reacting 3,1l-diketo-4,l7(20)-pregnadiene-2l-oic acid methyl ester with piperidine is productive of 3-piperidyl-11-keto- 3,5,l7(20)-pregnatriene-21-oic acid methyl ester. For a comparable yield of product, the employment of somewhat more vigorous reaction conditions than those described in Example 1 is usually necessary.

Similarly, other 3-amino derivatives of this and other starting 3,1l-diketo-4,17(20)-pregnadiene-21-oic acid esters are prepared by reacting the selected amine with a 3,11-diketo-4,l7(20)-pregnadiene-21-oic acid alkyl ester according to one of the procedures described in Example 1. Compounds thus-produced include 3-amino-11-keto- 3,5,17(20)-pregnatriene-21-oic acid esters wherein the amino group is pyrrolidyl, 2-methyl-pyrrolidyl, 3-methylpyrrolidyl, 2-ethylpiperidyl, 3-rnethylpiperidyl, and other alkyl pyrrolidyl or alkyl piperidyl radicals, and the ester group is methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, phenylethyl, benzyl, hexyl, heptyl, octyl, or the like. Employment of 3 ,1 1-diketo-4, 17 (20 -pregnadiene-2 l -oic acid ethyl ester and pyrrolidine is productive of the 3- pyrrolidyl 11 keto 3,5 ,17( 20)-pregnatriene-21-oic acid ethyl ester.

Example 3.3-piperidyl-1 1 a-hydroxy-3,5 ,1 7 (20 -pregnatriene-ZI-oic acid ethyl ester Following the procedure described in Example 1, 3- keto-llot-hydroxy-4,17(20)-pregnadiene-21-oic acid ethyl ester, which may be prepared by reacting lloc-hYdI'OXY- 21,21-dibromo-2leethoxy-oxyalylprogesterone with sodium ethoxide in ethanol, is reacted with about seven molar equivalents of piperidine in the presence of about 0.05 molar equivalent of para-toluenesulfonic acid, using refluxing benzene as a solvent, is productive of 3-piperidyl- 11u-hydroxy-3,5,17(20)-pregnatriene-2l-oic acid ethyl ester.

Similarly, other esters of 3-piperidyl-llu-hydroxy- 3,5,17(20)-pregnatriene-2l-oic acid, especially alkyl esters which are preferably lower-alkyl, are prepared by reacting the selected ester of 3-keto-11a-hydroxy-4,17(20)- pregnadiene-Zl-oic acid with piperidine in the manner described in Example 3, to produce the methyl, ethyl, propyl,

isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, phenylethyl, benzyl, octyl, or like-ester of 3-piperidyl-11a-hydroxy-3,5,17(20)-pregnatriene-21-oic acid, especially 3- piperidyl 1 la hydroxy-fa ,5 17 (20) pregnatriene-2 l-oic acid methyl ester and 3-piperidyl-11ot-hydroxy-3,5,17(20)- pregnatriene-Zl-oic acid ethyl ester. Substituting a C- alkyl substitutedpiperidine for the piperidine used in Example 3 is productive of the corresponding C-alkyl subst-ituted piperidyl B-enamine steroid.

Example 4.-3-pyrr0lidyl-1 1 fi-hydrxy-3,5 ,1 7(20) -pregnatriene-ZI -0ic acid methyl ester 5 .3-pyrr0lidyl-1 1 [3,21 -dihydr0xy-3,5 ,1 7(20 pregnatriene Example The reaction mixture resulting from the reaction of two grams of 3,11-diketo-4,17(20)-pregnadiene-21-oic acid methyl ester with two milliliters of pyrrolidine in 150 milliliters of benzene for three hours in the manner described in Example 1 was mixed at ten degrees centigrade with two grams of lithium aluminum hydride in 100 milliliters of ether by the dropwise addition of the latter thereto. The resulting mixture was maintained at about ten degrees centigrade for one-half hour. Fifty milliliters of water was then added dropwise thereto, whereafter the solvent layer was separated and the solvent removed therefrom. The resulting residue was triturated with ethyl acetate to give 0.88 gram of crystals, a yield of 41 percent of the theoretical, of 3-pyrrolidyl-115,21-dihydroxy- 3,5,17-(20)-pregnatriene, melting at 211 to 219 degrees centigrade. The mother liquor yielded an additional 0.45 gram of an oil having a similar infrared absorption curve. Recrystallization of these crystals produces 3-pyrrolidyl- 1.113,21-dihydroxy-3,5,l7(20)-pregnatriene melting at 228 to 232 degrees centigrade and having an [M of minus 88. degrees in chloroform.

Similarly, 3 pyrrolidyl-,1 1,3,21-dihydroxy-3 ,5 1 7 (20 prcgnatriene is prepared by reacting other esters of 3- pyrrolidyl-l1-keto-3,5,17(2 ))-pregnatriene-21-oic acid or of 3-pyrrolidyl-1lp-hydroxy-B ,5 17 20) -pregnatriene-2 1 oic acid with lithium aluminum hydride in a suitable solvent, avoiding prolonged contact with water, acid, or base, and especially mineral acid to ensure optimum yield of desired product.

Other 3-amino-11B,21-dihydroxy-3,5,17(20)-pregnatricues are prepared by reacting the methyl or other selected ester of a 3-amino-11-keto-4,17(20)-pregnadiene-2l-oic acid or of a 3-amino-11fi-hydroxy-4,17(20)-pregnadicne- 21 -0ic acid, wherein the amino. group is pyrrolidyl, piperidyl, C-alltyl substituted pyrrolidyl, or C-alkyl substi-. tuted piperidyl, preferably pyrrolidyl, with lithium aluminumhydride the manner illustrated above, the amino group of tie resulting product corresponding to the amino group of the starting selected steroid.

Example 6 .-3 -pyrr0lidyl-1 1 u,21-dihydr0xy-3,5,1 7(2'0 pregmttrienev 3-pyrrolidyl-l l 1,21-dihydroxy-3,5,17(2O)-pregnatriene is prepared by substituting 3-pyrrolidyl-11ix-hydroxy- 3,5 ,17(20)-pregnatriene-21-oic acid methyl ester or other alkyl ester for the 3-pyrrolidyl-11-ketq-3,5,17 (20)-pregnatriene-Zl-oic acid methyl ester used as the starting steroid. in the reaction described in Example 5.

Similarly, other 3-amino-11oc,21-dihydroxy-3,5,17(20)- pregnatrienes are prepared by substituting other 3-amino- 11a-hydroxy-3,5,17(20)-pregnatriene-21-oic acid alkyl esters wherein the aminogroup is piperidyl, or C-alkyl substituted pyrrolidyl or piperidyl, and the alkyl ester is methyl, ethyl, propyl, phenyl, benzyl, phenylethyl, butyl, amyl, hexyl, heptyl, octyl, or the like, for the 3-pyrro1idyl- 11a-hydroxy-3,5,17(20)-pregnatriene-21-oic acid methyl ester used as starting material in Example 6.

Example 7.11fi,21-dihydr0xy-4,1 7 (20) -pregnadiene-3- one A. The solvent layer of the reaction product, resulting from the reaction of 2.28 grams of 3-pyrrolidyl-11-keto- 3,5,17(20)-pregnatriene-21-oic acid methyl ester in ten milliliters of benzene with 0.68 gram of lithium aluminum hydride in milliliters of ether followed by hydrolysis with fifty milliliters of water, was freed of solvent by distillation at reduced pressure leaving a residue of crude 3 pyrrolidyl 115,21 dihydroxy 3,5,17 (20) pregnatriene. This residue was suspended in milliliters of methanol to which was added 25 milliliters of a five percent aqueous sodium hydroxide solution and the Whole maintained at between 42 and 46 degrees centigrade for fifteen minutes whereafter the mixture was neutralized with acetic acid. The methanol was distilled from the mixture and the residue stirred with fifty milliliters of water. The slurry was extracted with three fifty-milliliter portions of ether which were then combined and the ether distilled therefrom. This gave 1.67 grams, a yield of 88 percent of the theoretical based on the starting 3 pyrrolidyl 11 keto 3,5,17(20) pregnatriene 21 oic acid methyl ester, of 11fi,21-dihydroxy-4,17(20)- pregnadiene-3-one which, after crystallization from ethyl acetate, melted at 151 to 153 degrees centigrade and weighed 1.15 grams, a yield of 61 percent of the theoretical calculated on the starting 3 pyrrolidyl 11 keto 3,5,17(20) pregnatriene 21 oic acid methyl ester.

B. A suspension of 410 milligrams of 3-pyrrolidyl- 11/3,21-dihydroxy-3,5,17(20)-pregnatriene in 55 milliliters of methanol was heated 35 to forty degrees centigrade with three milliliters of a five percent aqueous sodium hydroxide solution until solution was complete, the time of heating being less than ten minutes. The resulting solution was cooled, neutralized with acetic acid, and the solvent distilled at reduced pressure. The residue was mixed with water and then repeatedly extracted with ether. The ether extracts, after evaporation of the solvent, yielded 343 grams, a 94.4 percent yield of the theoretical, of 11fi,21-dihydroxy-4,17(20)-pregnadiene-3-one melting at 150 to 153 degrees centigrade which, after recrystallization from ethyl acetate, melted at 155 to 157.5 degrees centigrade and weighed 225 milligrams.

C. A solution of 6.0 grams of 3,11-diketo-4,17(20)- pregnadiene-Zl-oic acid methyl ester, six milliliters of pyrrolidine, and milligrams of para-toluenesulfonic acid in 120 milliliters of benzene were heated at the reflux temperature of the mixture for one hour with the concomitant removal of the water of reaction. The solvent was distilled from the mixture to leave a residue consisting essentially of 3-pyrrolidyl-3,5,17(20)-pregnatriene-Zl-oic acid methyl ester.

This residue was dissolved in thirty milliliters of benzene and ten milliliters of ether, a suspension of 2.2 grams of lithium aluminum hydride in 350 milliliters of ether was added thereto over a period of five minutes, and the mixture was stirred at room temperature for 1.5 hours. Twenty milliliters of ethyl acetate was added to destroy excess lithium aluminum hydride, followed by thirty milliliters of water. The ether and benzene were distilled at reduced pressure from the mixture to leave a residue consisting essentially of 3-pyrrolidyl-l1fi,21-di- 13 hydroxy-3,5,17(20)-pregnatriene and inorganic material.

This crude distillation residue was mixed with 400 milliliters of methanol at forty degrees centigrade until solution was efiected. Seventy milliliters of an aqueous five percent sodium hydroxide solution was added there to and heating of the mixture at about forty degrees centigrade was continued for ten minutes. The solution was neutralized with acetic acid and the solvent distilled therefrom at reduced pressure and at a temperature below 45 degrees Centigrade. The residue was mixed with 100 milliliters of water containing ten milliliters of concentrated hydrochloric acid, filtered and washed with water to give 4.23 grams of 11p,21-dihydroxy-4,17(20)-preg nadiene-3-one melting at 156 to 158 degrees centigrade, a yield of 76.1 percent of the theoretical, based on the starting 3,1 1-diketo-4, 17 (20 -pregnadiene-21-oic acid methyl ester. The aqueous filtrate contained 1.1 grams of solids which, after extraction with ethyl acetate and chromatographing over Florisil synthetic magnesium silicate, yielded an additional amount of 11fl,2l-dihydroxy- 4,17(20)-pregnadiene-3-one.

115,21-dihydroxy-4, 17 (20)-pregnadiene-3-one is also prepared by substituting another 3-amino-11/3',21-dihydroxy-3,5,17(20)-pregnatriene, wherein the amino group is piperidyl, 2'-rnethyl-piperidyl, 3-ethylpiperidyl, 2'- methylpyrrolidyl, 3'-isopropylpyrrolidyl, or the like, for the 3-pyrrolidyl-1 15,2 1-dihydroxy-3,5, 17 (20) -pregnatriene used in the reaction described in Example 7C.

1 1a,21-dihydroxy-4, 17 (20)-pregnadiene-3-one is prepared by substituting 3-pyrrolidyl-11u,2l-dihydroxy- 3,5,17(20)-pregnatriene or like 3-amino-l1a,21-dihydroxy-3,5,17(20)-pregnatriene for the 3-pyrrolidyl- 1lfl,2l-dihydroxy-3,5,17(20)-pregnatriene used in Example 7.

D. Repeating the reaction described in Example 7C, but substituting five percent aqueous hydrochloric acid for the five percent aqueous sodium hydroxide used to hydrolyze the 3-pyrrolidyl-l16,2l-dihydroxy-3,5,l7(20) pregnatriene, is productive of llfi,2l-dihydroxy-4,l7(20)- pregnadiene-3-one. Other aqueous acids which may be used in this hydrolysis reaction include phosphoric, sulfuric, acetic, and the like.

Example 8.11fi,21-dihydr0xy4,1 7 (20 -pregnadiene-3- one and its conversion to v 1 J/B-hydroxy-Zl -acetxy- 4,17(20)-pregnadiene-3-0ne A. A solution of 3.0 grams of 3,11-diketo-4,17(20)- pregnadiene-Zl-oic acid methyl ester and three milliliters of pyrrolidine in sixty milliliters of benzene was heated at its refluxing temperature for one hour with the concomitant removal of the water of reaction, producing 3-pyrrolidyl-l 1-keto-3,5, 17 (20 -pregnatriene--21 oic acid methyl ester. The solvent was distilled from the resulting mixture at reduced pressure and the residue dissolved in a mixture of fifteen milliliters of benzene and ten milliliters of ether. To this solution was added 1.1 grams of lithium aluminum hydride suspended in 175 milliliters of ether. The resulting solution was stirred for 1.5 hours at about 26 degrees centigrade. Ten milliliters of ethyl acetate followed by fifteen milliliters of water were added to the solution and the solvent was distilled therefrom at reduced pressure. The residue, consisting essentially of inorganic salts and 3-pyrrolidyl-11B,21-dihydroxy-3,5,l7(20)-pregnatriene, was suspended in 200 milliliters of methanol and 35 milliliters of a five percent aqueous sodium hydroxide solution was added to the suspension. The whole was then heated at forty to 45 degrees Centigrade for ten minutes. The cooled mixture was neutralized with acetic acid and the methanol then distilled therefrom. The residue was stirred with fifty milliliters of methylene chloride and 100 milliliters of water containing fifteen milliliters of concentrated hydrochloric acid. The methylene chloride solution was separated from the aqueous layer, which was then extracted with another portion of methylene chloride, and the extract added to the original methylene chloride solution. The solvent was evaporated from the extracts leaving 2.86 frams of crude l1fi,21-dihydroxy-4,17(20)pregnadiene-B-one.

The 2.86 grams of l1,8,2l-dihydroxy-4,l7(20)pregnadiene-3-one thus-obtained was treated with five milliliters of acetic anhydride in ten milliliters of pyridine at 26 degrees centigrade for four hours. The resulting mixture was mixed with ten milliliters of water with cooling to hydrolyze the excess acetic anhydride, and the solution extracted with methylene chloride. The extract was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and finally water. The methylene chloride was distilled from the solution and the 2.59 gram residue, representing an 82.8 percent yield, based on starting 3,11diketo-4,17(20)-pregnadiene- 21-oic acid methyl ester, was recrystallized from a mixture of acetone and Skelly-solve B hexane hydrocarbons to give 1.60 grams, a yield of 51 percent of the theoretical, of 1 1,8-hydroxy-21-acetoxy-4,17(20)-pregnadiene-3- one melting at 185 to 188 degrees centigrade. The mother liquors yielded a further 270 milligrams of product melting at to degrees centigrade.

B. Repeating the reaction in exactly the same manner as described in Example 8A, but using 33% times the amount stated therein, there was obtained 70.6 grams, a yield of 67.8 percent of the theoretical, calculated on the starting 3,1l-diketo-4,17(20)-pregnadiene-21-oic acid methyl ester, of 1l/3-hydroxy-21-acetoxy-4,l7(20)-pregnadiene-B-one in three crops, the first of which melted at 189 to 192.5, the second at 187 to 192.5, and the third at 186 to 190.5 degrees centigrade.

118,1704,2LTRIHYDROXY-l-PREGNENE-B-ONE (KENDALL'S COMPOUND F) To a stirred suspension of 0.124 gram (0.00033 mole) of llfi-hydroxy-Zl-acetoxyl, 17 (20)-pregnadiene-3-one in two milliliters of tertiary butyl alcohol was added 0.26 milliliter of a 2.6 molar solution of hydrogen peroxide in tertiary butyl alcohol and 0.30 milliliter of a solution of 1.00 gram of osmium tetroxide in 100 milliliters of tertiary butyl alcohol. An additional 0.50 milliliter of the above described osmium tetroxide solution was added to the reaction mixture during the next thirty hours. After the first four hours of reaction time the reaction mixture darkened and became homogeneous. The reaction mixture was stirred and maintained at room temperature for an additional 84 hours, whereafter water and methylene chloride were added thereto. The whole was distilled at reduced pressure to remove the organic solvents and the product was extracted from the residue with methylene chloride, whereafter the extract was freed of solvent by evaporation. The residue, after dissolving in a mixture of five milliliters of methanol and one milliliter of a solution of 0.30 gram of sodium sulfite in five milliliters of water, was heated on a steam bath for thirty minutes. The 11p,17a,21-trihydroxy-4-pregnene- 3,20-dione was separated therefrom by extraction with methylene chloride, which was thereafter removed by distillation in vacuo. The 0.101 gram of residue consisted of about fifty percent of the desired 1l 8,l7a,21- trihydroxy-4-pregnene-3,20-dione (Kendalls compound F).

This application is a continuation-in-part of application Serial No. 358,201, filed May 28, 1953.

' It is to be understood that this invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 3-amino-l 1-oxygenated-3,5,17 (20) -pregnatriene-2l- 15 oic acid alkyl esters represented by the following formula:

C O O-lower-alkyl OHa O O-1ower-a1ky1 OH I wherein n is a whole number from four to five, inclusive.

3. A 3-amino-11-hydroxy-3,5,l7(20)-pregnatriene-21- oic acid alkyl ester represented by the following formula:

C O O-lower-alkyl H II wherein n is a whole number from four to five, inclusive.

4. A lower-alkyl ester of 3-pyrrolidyl-l1-l eto-3,5,17 (20)--pregnatriene-21-oic acid.

5. A iower-alkyl ester of 3-pyrrolidyl-1l-hydroxy- 3,5,17(20)-pregnatriene-21-oic acid.

6. A lower-alkyl ester of 3-pyrrolidyl-1lot-hydroxy- 3,5,].7(20)-pregnatriene-2i oic acid.

7. A lower-alkyl ester of 3-pyrrolidyl-1lfi-hydroxy- 3,5,17(2G)-pregnatriene-2l-oic acid.

8. S-pyrrolidyl-ll-ketor3,5,17(20)-pregnatriene-2l-oic acid methyl ester.

9. 3-pyrrolidylll-keto-3,5,17(20) -pregnatriene-21-oic acid ethyl ester.

16. 3-pyrrolidyl-1 1 tt-hydroxy3 ,5 l 7 (20) -pregnatriene- 2l-oic acid methyl ester. i

1 1. 3-pyrrolidyl- 1 lu-hydroxy 3,5,l7(20)-pregnatriene- 2l-oic acid ethyl ester. 'i

l2. 3 pyrrolidyl-l 1 fi-hydroxy-B' ,5 l 7 (20 -pre gnatriene- Zl-oic acid methyl ester.

13. A process which comprises reacting an ester of a acid,

G O 0 R wherein R is selected from the group consisting of an a hydroxy group, a fi-hydroxy group, and a ketonic oxygen, and wherein COOR represents a carboxylic acid ester radical, with a cyclic alkylene amine represented, by the formula R NH wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce the corresponding ester of a 3- aminol1-oxygenated-3,5,17(20)-pregnatriene-21- oic 14. process which comprises reacting an alkyl ester of 3,11- diketo-4,17(20)-pregnadiene-2l-oic acid with a cyclic alkylene amine represented by the formula R NH wherein R is analkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce an alkyl ester of a 3-amino-1l-keto 3,5,17(20)-pregnatriene-2l-oic acid.

' 15."A process which comprises reacting a lower-alkyl ester. of 3,11 diketo-4,17(20)-pregnadiene-2l-oic acid with a cyclic alkylene, amine represented by the formula wherein n is a whole number from four to five, inclusive, to produce a lower-alkyl ester of a 3-amino-11-keto- 3,5,17(20)-pregnatriene-2l-oic acid.

16. The process of claim 15 wherein the water of reaction is removed from the reaction mixture.

17. The process of claim 15 wherein/the cyclic alkylene amine is pyrrolidine.

' 18. The process of claim 15 wherein the cyclic alkylene amine is pyrrolidine and the starting steroid is 3,11- diketo-4,'l7(20)--pregnadiene-21-oic acid methyl ester.

19. The process of claim 15 wherein the cyclic alkylene amine is pyrrolidine, the starting steroid is 3,11-diketo- 4,17(20)-pregnadiene-21-oic acid methyl ester and the water of reaction is removed from the reaction mixture.

20. A process which comprises reacting an alkyl ester of 3-keto-1l-hydroxy 4,l7(20)-pregnadiene-2l-oic acid with a cyclic alkylene amine represented by the formula R NH A (CH2) In NH wherein n is .a whole number from four to five, inclusive,

amine is pyrrolidine and the starting steroid is 3-keto- 1lor-hydroxy-4,l7(20)-pregnadiene-2l-oic acid methyl ester.

24. The process of claim 21 wherein the cyclic alkylene amine is pyrrolidine, the starting steroid is 3-k6t0-11ochydroxy-4,l7(20)-pregnadiene-2l-oic acid methyl ester and the water of reaction is removed from the reaction mixture.

25. The process which comprises reacting 3,1l-diketo- 4,17(20)-pregnadiene-2l-oic acid methyl ester with pyrrolidine in an organic solvent, at a temperature between about 25 and 150 degrees centigrade, in the presence of an acid catalyst, and with the removal of the water of reaction from the reaction mixture, to produce 3-pyrrolidyl-l l-keto-3,5, 17 (20) -pregnatriene-2l-oic acid methyl ester.

26. The process which comprises reacting 3-keto-11ahydroxy-4,17(20)-pregnadiene-21-oic acid methyl ester with pyrrolidine in an organic solvent at a temperature between about 25 and about 150 degrees centigrade, in the presence of an acid catalyst, and with the removal of the water of reaction from the reaction mixture, to produce 3-pyrrolidyl-1 1a-hydroxy-3 ,5 17 20 -pregnatriene-Zl-oic acid methyl ester.

27. A process which comprises reacting an ester of a 3-keto-11-oxygenated-4,17(20)-pregnadiene-2l-oic acid, represented by the following formula:

wherein R is selected from the group consisting of an a-hydroxy group, a p-hydroxy group, and a ketonic oxygen, and wherein --COOR represents a carboxylic acid ester radical, with a cyclic alkylene amine represented by the formula wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce the corresponding ester of a 3-amino-l1-oxygenated-3,5,l7(20)-pregnatriene-2loic acid, reacting the thus-produced B-amino-ll-oxygenated-3,5,17()-pregnatriene-2l-oic acid ester with lithium aluminum hydride in an organic solvent, and decomposing any excess lithium aluminum hydride and organo-met-al complexes to produce a 3-amino-1l,2l-dihydroxy-3,5,17(20)-pregnatriene.

28. A process which comprises reacting a lower-alkyl ester of 3,11-diketo-4,17(20)-pregnadiene-21-oic acid with a cyclic alkylene amine represented by the formula wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce a loWer-alkyl ester of a 3-amino-ll-keto-3,5,17(20)-pregnatriene-21-oic acid, reacting the thus-produced 3-amino-11-keto-3,5,l7(20)- pregnatriene-Zl-oic acid lower-alkyl ester with lithium aluminum hydride in an organic solvent, and decomposing any excess lithium aluminum hydride and organometal complexes to produce a 3-amino-1 118,21-dihydroxy- 3,5,17(20) -pregnatriene.

29. A process which comprises reacting a lower-alkyl ester of 3,1l-diketo-4,17(20)-pregnadiene-2l-oic acid with a cyclic alkylene amine represented by the formula wherein n is a whole number from four to five, inclusive, to produce a lower-alkyl ester of a 3-amino-l1- l;eto-3,5,l7(20)-pregnatriene-2l-oic acid, reacting the thus-produced 3-amino-l1-keto-3,5,17(20)-pregnatriene- 2l-oic acid lower-alkyl ester with lithium aluminum hydride in an organic solvent, and decomposing any excess lithium aluminum hydride and organo-metal complexes to produce a 3-amino-l1,6,21-dihydroxy-3,5,l7(20)-pregnatriene.

30. The process of claim 29 wherein the cyclic alkylene amine is pyrrolidine. g

31. The process of claim 29 wherein the cyclic alkylene amine is pyrrolidine and the starting steroid is 3,1l-diketo- 4,17(20)-pregnadiene-2l-oic acid methyl ester.

32. A process which comprises reacting a lower-alkyl ester of 3-ketoll-hydroxy-4,l7(20)-pregnadiene-2l-oic acid with a cyclic alkylene amine represented by the formula wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce a lower-alkyl ester of a 3-amino-l 1-hydroxy-3,5 ,17 (20)-pregnatriene-2l-oic acid, reacting the thus-produced 3-amino-11-hydroxy 3,5,17(20)-pregnatriene-2l-oic acid lower-alkyl ester with lithium aluminum hydride in an organic solvent, and decomposing any excess lithium aluminum hydride and organo-metal complexes to produce a 3-amino-1l,2l-dihydroxy-3,5,l7(20)-pregnatriene.

33. A process which comprises reacting a lower-alkyl ester of 3-keto-1 1-hydroxy-4, 17 (20 -pregnadiene-2 l-oic acid with a cyclic alkylene amine represented by the formula wherein n is a whole number from four to five, inclusive, to produce a lower-alkyl ester of a 3-amino-11- hydroxy-3,5,l7(20)-pregnatriene-21-oic acid, reacting the thus-produced 3-amino 11 hydroxy 3,5,17(20) pregnatriene-Zl-oic acid lower-alkyl ester with lithium aluminum hydride in an organic solvent, and decomposing any excess lithium aluminum hydride and organo-metal complexes to produce a 3 amino 11,21 dihydroxy- 3,5,l7(20)-pregnatriene.

34. The process of claim 33 wherein the cyclic alkylene amine is pyrrolidine.

35. The process of claim 33 wherein the cyclic alkylene amine is pyrrolidine and the starting steroid is 3-ketO-llochydroxy-4,l7(20)-pregnadiene-2l-oic acid methyl ester.

36. A process which comprises reacting an alkyl ester of 3-1l-diketo-4,17(20)-pregnadiene-21-oic acid With a cyclic alkylene amine represented by the formula A R NH wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six carbon atoms, inclusive, to produce an alkyl ester of a 3-amino-1l-keto-3,5,17(20)-pregnatriene-21-oic acid, reacting the thus-produced 3-amino-l1-keto-3,5,17(20)- pregnatriene-Zl-oic acid alkyl ester with lithium aluminum hydride in an organic solvent, decomposing any excess lithium aluminum hydride and organo-metal complexes, and hydrolyzing the thus-produced 3-amino-llfi,- 2l-dihydroxy-3,5,l7(20)-pregnatriene with aqueous solu- 19 tion to produce l1p,;l-dil;ydro ry-4,17(20)-pregnadiene- 3-one.

37. The, process of claim 36 wherein the cyclic alkylene amine is pyrrolidine.

38. The process of claim 36 wherein the cyclic alkylene amine is pyrrolidine and the starting steroid is 3,1l-diketo- 4,17(20)-pregnadiene-21-oic acid methyl ester.

39. A process which comprises reacting a lower-alkyl ester of S-keto-l1-hydroXy-4,l7(20)-pregnadiene-21-oic acid with a cyclic alkylene amine represented by the formula A RNH wherein R is an alkylene group which, together with the nitrogen atom, forms a ring containing from five to six members, inclusive, to produce an alkyl ester of 3-aminol 1-hydr0Xy-3,5,17(2 0)-pregnatriene-21-oic acid, reacting the thus-produced 3-amino-11-hydroxy-3,5,17(20)-pregnatriene-Zl-oic acid alkyl ester with lithium aluminum hydride in an organic solvent, decomposing any excess lithium aluminum hydride and organs-metal complexes, and hydrolyzing the thus-produced 3-amino-11,21-dihydroxy-3,5,17(20)-pregnatriene with aqueous solution to produce an 11,21-dihydroxy-4, 17 (20 -pregnadiene-3-one. 40. The process of claim 39 wherein the cyclic alkylene amine is pyrrolidine.

41. 3-amino 11,21 dihydroxy 3,5,17(20) pregnatrienes represented by the following formula:

CHZOH H II wherein R is an alkylene group containing less than nine carbon atoms and having a 4 to 5 carbon atom bridge between the valences which, together with the nitrogen atom,

forms a ring which contains from five to six members,

inclusive.

42. A 3-amino-11,21-dihydroxy 3,5,17() pregnatriene represented by the following formula:

wherein n is a whole number from four to five, inclusive.

43. S-piperidyl ;,21 dihydr0xy-3,5,17(20) -pregnatriene.

44. 3-piperidyl 11,8,21 dihydroxy-3,5,17(20).-pregnatriene.

45. 3-pyrrolidyl 1111,21 dihydroxy-3,5,17(20)-pregnatrienc.

46. 3-pyrrolidyl 11 3,21 dihydroxy-3,5,1 7(20)-pregnatriene.

47. The process which comprises reacting an ester of a 3-amino-ll-keto- 3, 5',l7(20) pregnatriene-Zl-oic acid represented by the following formula:

wherein R is an alkyleue group which, together with the nitrogen atom, forms a ring which contains from five to six members, inclusive, and wherein COOR is a carboxylic acid ester radical, with lithium aluminum hydride in an organic solvent and decomposing any excess lithium aluminum hydride and organo-metal complexes to produce a 3-amino-l1B,21-dihydroxy 3,5,17(20) pregnatriene.

48. The process which comprises reacting a lower-alkyl ester of 3-pyrrolidyl-11-keto-3,5,17(20)-pregnatriene-21- oic acid with lithium aluminum hydride and decomposing any excess lithium aluminum hydride and organo-metal complexes with water to produce 3-pyrrolidyl- 113,21- dihydroxy-3,5, 17 (20) pregnatriene.

No references cited. 

1. 3-AMINO-11-OXYGENATED-3,5,17(20)-PREGNATRIENE-21OIC ACID ALKYL ESTERS REPRESENTED BY THE FOLLOWING FORMULA: 